Prevention of Progression in Diabetic Nephropathy

Abstract

In Brief

Diabetic nephropathy is the most common cause for end-stage renal disease
and for patients entering into chronic dialysis care. It occurs in
25–40% of patients with diabetes. Risk factors include hyperglycemia,
hypertension, genetic predisposition, glomerular hyperfiltration, proteinuria,
the renal renin-angiotensin system, advanced glycation end-products, and
possibly reduced nephron number and lipid disorders. Prevention of diabetic
nephropathy is crucial. Tight control of diabetes, blood pressure treatment to
systolic pressure of < 130 mmHg, reduction of proteinuria, and treatment
with drugs that inhibit the renin-angiotensin system are all associated with
prevention of or delay in progression of diabetic kidney injury.

A quarter of a century ago, C.E.
Mogensen1 made the
unique observation that lowering blood pressure in patients with type 1
diabetes and diabetic nephropathy reduced the rate of loss in kidney function.
In that study of five insulin-dependent proteinuric men with long-standing
diabetes, blood pressure was lowered with combinations of furosemide,
prazosin, hydralazine, and β-blockers. This observation presaged what has
become a crucial intervention in diabetic nephropathy: that lowering systemic
blood pressure has been repeatedly shown to alter the course of diabetic
kidney disease. Great progress has been made in understanding some of the
other mechanisms of this disorder and in delaying its clinical expression and
preventing its progression.

The importance of diabetic nephropathy as a cause for patient morbidity and
mortality is well known. Diabetic nephropathy occurs in ∼ 30% of people
with type 1 diabetes and 25–40% of people with type 2 diabetes, often
irrespective of glycemic control. Diabetic nephropathy is the single most
common cause of end-stage renal disease (ESRD) in the United States,
accounting for > 50% of new cases of renal failure. Patients who have
diabetes and reach ESRD have a poor prognosis because of high cardiovascular
events. Thus, early identification of patients who have diabetes and are at
high risk for nephropathy is mandatory in order to prevent the development or
progression of diabetic nephropathy.

This article will review what is known about the major mechanisms and risk
factors promoting renal injury in diabetes and will summarize the
evidence-based recommendations for preventing progression.

MECHANISMS OF RENAL INJURY IN DIABETES

The mechanisms of renal injury in diabetes are listed in
Table 1 and discussed in more
detail in this section.

Hyperfiltration Injury

What is known about how renal disease develops and progresses has changed
in recent years. Previously, it was thought that kidney injury was simply the
result of various insults such as immune complexes, ischemia, toxins, or, in
the case of diabetes, some metabolic product (e.g., advanced glycoslyation end
products [AGEs]). Now, however, we know that progressive renal disease is
caused by the combination of an initial or ongoing injury and a final common
pathway of maladaptive response to that injury, a response that involves
changes in glomerular hemodynamics and the release of cytokines and vasoactive
hormones.

Research has shown that the following sequence of events leads to chronic
kidney failure. Most renal diseases result from an initial injury that causes
a loss of functioning nephrons. Each remaining nephron must then work harder,
filtering more blood per minute to maintain homeostasis. To do this, the
kidney secretes intrarenal vasoactive hormones, such as prostaglandin E2, that
preferentially dilate afferent arterioles and other hormones, such as
angiotensin and catecholamines, that constrict efferent arterioles. Each
glomerulus therefore receives more blood at a higher pressure and therefore
filters more fluid into tubules. This situation, called hyperfiltration,
damages the glomerular capillary in subtle ways, produces mesangial cell and
glomerular basement membrane injury, and stimulates release of cytokines. All
of these effects can produce further relentless injury and scarring of the
remaining nephrons with further nephron loss. In addition, most renal diseases
are accompanied by systemic hypertension and proteinuria, both of which are
thought to accentuate this ongoing maladaptive intrarenal response. Systemic
hypertension, in the setting of a glomerulus with dilated afferent and
constricted efferent arterioles and abnormal basement membrane permeability
(the hyperfiltration state), causes even greater degrees of glomerular
pressure and injury. Proteinuria results in increased proximal tubular protein
uptake, which causes an inflammatory response in the interstitium.

Diabetic renal disease begins not with loss of nephrons, but rather with
glomerular hyperfiltration and increased glomerular filtration rate (GFR).
This hyperfiltration, which has been shown to be present in early phases of
both type 1 and type 2 diabetes, may exist for several
years.2,3
Several studies have shown that hyperfiltration is associated with the degree
of hyperglycemia.

However, hyperfiltration does not always predict the future development of
kidney injury in diabetes. In vulnerable patients destined for diabetic kidney
disease, GFR begins to decrease as microalbuminuria appears. When overt
proteinuria occurs, most individuals with diabetes have clinically decreased
GFR. At this point in the course of diabetic kidney disease, loss in nephrons
occurs, with the maladaptive events described above. Although the overall GFR
is decreased, the glomerular filtration rate per nephron is increased, and
hyperfiltration injury continues. This leads to further nephron loss,
proteinuria, glomerular and interstitial scarring, and progressive renal
failure.

Although diabetes is often accompanied by hyperglycemia, hypertension, and
altered lipids, surprisingly, most individuals with type 1 or type 2 diabetes
do not develop diabetic nephropathy. This suggests that other factors are
involved.

Genetic Factors

It is clear that there are genetic factors in the risk for diabetic
nephropathy. Data from the Diabetes Control and Complications Trial
(DCCT)4 have shown
that up to 35% of patients develop diabetic nephropathy, regardless of their
level of glycemic control. Seaquist et
al.5 showed that
siblings of patients with type 1 diabetes who also have diabetes have a
fourfold greater chance of developing diabetic nephropathy. In African
Americans, Freedman et
al.6 have also shown
that ESRD is five times higher in relatives of patients with type 2 diabetes
with ESRD. Among diabetic Pima Indians, 14% of descendants of parents without
nephropathy develop diabetic nephropathy, whereas the incidence of nephropathy
is 23% if one parent had proteinuria and 46% if both parents had
nephropathy.7

These observations alone do not prove a genetic contribution for diabetic
nephropathy but may illustrate a socioeconomic/cultural clustering. However,
several investigators employing molecular genetic techniques have performed
linkage analyses to explain the vulnerability for diabetic nephropathy. Thus
far, evidence for linkage to diabetic nephropathy has been detected on
chromosomes 3q, 10q, and
18q.8

Reduced Number of Nephrons

Several animal and human
studies9–11
have shown that reduced numbers of glomeruli at birth are associated with the
eventual development of hypertension or kidney disease. The suggestion is that
for individuals who start with a reduced number of nephrons, any subsequent
renal injury will render them more vulnerable to progressive nephropathy.
Diabetes in pregnant rats diminishes kidney weight and nephron number in their
offspring.12,13
This finding can be imitated by exposing pregnant rats to hyperglycemia at the
time fetal renal tissue is developing. If this is also true for humans,
hyperglycemia in pregnant women may predispose their children to both
hypertension and renal disease.

AGEs

In the setting of diabetes and long-standing hyperglycemia, free amino
groups of proteins are nonenzymatically modified by glucose and its
metabolites to form Schiff bases that eventually lead to the formation of
AGEs. AGEs may produce functional changes in the kidney by crosslinking with
the glomerular basement membrane and other vascular
membranes.14
AGE-binding proteins may also be involved. The best defined of these is the
receptor for AGEs
(RAGE).15 Binding
of AGEs to RAGEs activates cell signaling mechanisms coupled to increased
transforming growth factor β (TGF-β) and vascular endothelial growth
factor (VEGF) expression, which are increased in diabetic nephropathy and are
thought to contribute to diabetes
complications.16,17

Several recent studies have shown that angiotensin receptor blockers (ARBs)
and ACE inhibitors reduce AGEs and alter functioning of
RAGEs.18,19
These effects suggest that these drugs provide renal protection by inhibiting
the expression of TGF-β and VEGF mediated by AGEs and RAGEs that leads to
the endothelial injury and fibrosis that is so characteristic of diabetic
nephropathy.

Hyperglycemia

The hyperglycemic state itself is known to be a significant risk factor for
diabetic nephropathy. Glycemic control in both type 1 and type 2 diabetes has
been associated with reduced appearance of diabetic nephropathy
(microalbuminuria).20,21
The reasons for this are likely multiple. At least two clinical observations
inform us about possible mechanisms.

The first is that the hyperglycemic state seems to sensitize the
endothelium to injury from elevated blood pressure. In type 2 diabetes,
lowering blood pressure, regardless of the type of agent used to do so,
retards the onset and progression of diabetic
nephropathy.22 In
type 1 diabetes, Lurbe et
al.23 have noted
that an insufficient decline in nighttime blood pressure (nondipping) preceded
the onset of microalbuminuria. The second observation is that successful
pancreas transplant that results in normal insulin regulation and
normoglycemia is associated with a reversal of the lesions of diabetic
nephropathy.24

Proteinuria

Proteinuria accompanies most progressive renal diseases. Proteinuria,
either microalbuminuria or macroalbuminuria, accompanies diabetic nephropathy.
In general, the greater the proteinuria, the more likely the disease will
progress. Many have considered proteinuria as simply a marker of significant
renal injury. Recent
studies,25,26
however, suggest that the proteinuria itself may contribute to progression of
renal disease.

Any glomerular injury that increases the permeability of the glomerular
basement membrane will allow plasma proteins to escape into the urine,
resulting in proteinuria. Some of these proteins are ingested by proximal
tubular cells, initiating an inflammatory response that contributes to
interstitial scarring. Several
investigators26–28
have shown that lisinopril and mycophenolate significantly reduce
proteinuria-induced inflammatory injury as well as the rate of disease
progression in normal rats with 1-5/6 nephrectomy (a procedure that reduces
functioning kidney tissue to < 25% of normal). This information implies
that any therapy, such as treatment with an ACE inhibitor or ARB, that reduces
proteinuria may have a benefit beyond that brought about by reduction in blood
pressure or alteration of glomerular hemodynamics.

Renal Renin-Angiotensin System

Past observations have shown that diabetes is a low-renin state, yet
diabetic nephropathy seems responsive to pharmacological blockade of the
renin-angiotensin system (RAS). It is now well appreciated that a local
(renal) RAS exists and is activated in diabetic individuals in the proximal
tubular epithelial
cells,29 mesangial
cells,30 and the
podocytes.31 It is
this intrarenal RAS that may explain the difference in dose-response curves
for blood pressure lowering and lowering of urinary protein excretion, namely,
that higher doses are needed for urinary protein lowering in experimental
animals and
humans.32

Systemic Hypertension

Of all of the mechanisms contributing to diabetic nephropathy, reduction of
blood pressure has been clearly shown to be an important and powerful
intervention. Multiple-treatment clinical trials in type 1 and type 2 diabetes
have confirmed that reducing blood pressure is associated with decreased
progression of diabetic nephropathy. In type 2 diabetes, blood pressure
lowering independent of the antihypertensive agent used retards onset and
progression of diabetic
nephropathy.22 In
animal models of diabetes, the degree and severity of diabetic nephropathy is
strongly linked to systemic blood pressure, being more marked in the obese
type 2 model than in the normotensive type 1 model (streptozotocin-induced
diabetes).33,34
In individuals with diabetes who have disordered autoregulation of the
microcirculation of the retina and kidney, systemic hypertension causes
barotrauma with endothelial injury.

Lipid Abnormalities

Patients with diabetes have a variety of disorders of plasma lipids. These
lipid abnormalities are known to contribute to cardiovascular risk. The role
of lipids in diabetic nephropathy is not clear. In animals with reduced
nephron number, dietary-induced hypercholesterolemia worsens glomerular
injury.35
Cholesterol-lowering drugs given to Zucker rats were associated with
attenuation of glomerular
lesions.36 Thus
far, a controlled trial to investigate whether lipid lowering will be
beneficial in diabetic nephropathy has not been reported.

TREATMENTS FOR REDUCING DIABETIC NEPHROPATHY

From the above discussion, it is clear that diabetic nephropathy is the
result of several contributing mechanisms, not all of which are operative in
most individuals with diabetes. Clearly, prevention of diabetes is the surest
way to prevent diabetic nephropathy. At this time, prevention of type 1
diabetes is not possible. Genetic factors in type 2 diabetes, if proven, are
not yet modifiable. As will be reviewed below, aggressive treatment of
patients with cardiovascular risk factors can reduce de novo type 2 diabetes.
If hyperglycemia during embryonic development is shown to cause reduced
nephron numbers in humans, prevention of hyperglycemia during pregnancy may be
protective from future renal injury, but this deduction has not been
tested.

At the moment, glycemic control, blood pressure lowering, and inhibition of
the RAS are the major treatment strategies once diabetes is present
(Table 2). What has research
shown to guide our treatments?

Evidence-Based Interventions to Prevent Development of Diabetes or
Prevent Diabetic Nephropathy

Preventing the Onset of Diabetes

Several large
studies37–40
have solidly documented that both ACE inhibitors and ARBs lower the risk of de
novo type 2 diabetes. These studies were criticized because in some studies
ACE inhibition or ARB therapy was compared to diuretics or β-blockers,
agents that could have increased the appearance of diabetes and thus made the
ACE inhibition or ARB agents appear more effective.

This issue was clearly resolved by the Valsartan Antihypertensive Long-term
Use Evaluation (VALUE)
trial.41 In this
trial, the use of the ARB valsartan versus amlodipine clearly demonstrated a
reduction in the appearance of type 2 diabetes. VALUE compared an ARB with
amlodipine, which is not known to have any adverse effect on the development
of diabetes. Pos-sible explanations for the favorable effect of inhibition of
RAS on de novo diabetes comes from a study by Lau et
al.42 showing that
RAS is present in β-cells of the pancreatic islets, that there is
dose-dependent inhibition of glucose-stimulated insulin release by angiotensin
2, and that this suppression is completely reversed by pretreatment with the
angiotensin type 1 receptor antagonist losartan but not by angiotensin type 2
receptor blockade.

Preventing the Appearance of Diabetic Nephropathy

Glycemic control

One of the earliest markers for diabetic nephropathy is microalbuminuria.
Because the presence of microalbuminuria is thought to be a manifestation of
renal and generalized endothelial injury and strongly predicts progressive
diabetic nephropathy and cardiovascular risk, preventing its development is
likely to be associated with prevention of progressive diabetic nephropathy
and possibly of cardiovascular disease. Hence, in diabetes, the appearance or
presence of microalbuminuria is used as an important indicator of effective
treatment intervention.

In type 1 and type 2 diabetes, the
DCCT21 and the U.K.
Prospective Diabetes Study
(UKPDS)20,
respectively, have shown a direct linear relationship between hyperglycemia
and both the development (as evidenced by microalbuminuria) and progression of
diabetic nephropathy (progression to macroalbuminuria or increasing serum
creatinine) in patients who already have diabetes. Both studies showed that
tight glycemic control was associated with a reduction in the appearance of
microalbuminuria. In the latter trial, any decrease of hemoglobin
A1c (A1C) by 1% was accompanied by a 37% decrease in the incidence
rate of micro- or macroalbuminuria and retinal complications. These and many
other observations have resulted in a recommendation from the American
Diabetes Association (ADA) that renoprotective glycemic values are A1C <
7%, preprandial blood glucose 90–130 mg/dl, and postprandial peak <
180 mg/dl.43

The oral hypoglycemic drugs rosiglitazone and pioglitazone, both
thiazolidinediones (TZDs), are used in the treatment of type 2 diabetes. These
drugs are agonists of the peroxisome proliferator–activated receptors
(PPARs). PPARs are nuclear hormone receptors and transcription factors. Three
different subtypes have been identified. These have been found to be crucial
factors in regulating diverse biological processes, including lipid
metabolism, insulin sensitivity, and cell growth and
differentiation.44

One of these subtypes, PPAR-γ, is also present in glomerular
mesangial cells.45
When compared to oral hypoglycemic agents, including metformin, glyburide, and
glibenclamide, all antidiabetic TZDs exhibit similar glycemic control but also
seem to provide superior protection against diabetic
nephropathy.46–48
This protection is likely a result of the systemic effect on glycemic control
as well as a direct local renal effect on mesangial cell function, possibly
related to the unique actions of these drugs on PPAR-γ. Support for this
conclusion comes from studies in animal models of both type 1 and 2 diabetes,
wherein PPAR-γ agonists have been shown to improve diabetic
nephropathy.49–52

In summary, it appears that angiotensin blockade reduces the onset of
diabetes in high-risk populations. Tight glycemic control in diabetic patients
lessens the appearance and progression of diabetic nephropathy. PPAR agonists
may provide additional protection against diabetic nephropathy beyond that
attributed to glycemic control.

Blood pressure control

The EUCLID (Eurodiab Controlled Trial of Lisinopril in Insulin Dependent
Diabetes) study53
in type 1 diabetic subjects did not detect any difference in the appearance of
microalbuminuria in patients treated with lisinopril versus placebo. However,
in a study of 1,204 subjects with hypertension and nonalbuminuric type 2
diabetes, Ruggenenti et
al.54 compared
trandolapril alone, trandolapril plus verapamil, verapamil alone, and placebo
in preventing the appearance of microalbuminuria. Trandolapril alone and in
combination with verapamil were much more effective in preventing the
appearance of microalbuminuria than verapamil alone or placebo. This benefit
occurred even though the levels of blood pressure control achieved were
identical in all groups, suggesting that inhibition of the RAS provided
protection in addition to that resulting from lowering of blood pressure. The
Appropriate Blood Pressure Control in Diabetes (ABCD)
trial22 found
significant reduction in the development of microalbuminuria in normotensive
but not hypertensive type 2 diabetic patients treated to the same goal blood
pressure with either nisoldipine or enalapril.

In the UKPDS, tight blood pressure control did not reduce the development
of microalbuminuria in type 2 diabetic
subjects.55 In the
Microalbuminuria Cardiovascular Renal Outcomes (MICRO)–Heart Outcomes
Prevention Evaluation (HOPE)
substudy56 there
was no difference in the development of microalbuminuria between groups who
received ramipril and placebo.

In summary, the above clinical trials do not clearly show that blood
pressure control in type 1 diabetic patients lessens the appearance of
microalbuminuria. In type 2 diabetes, at least two of the trials do indicate
that lowering blood pressure is associated with reduction in the appearance of
microalbuminuria, and they also suggest that this is best achieved with an
angiotensin-inhibiting regimen that may provide protection beyond that
resulting from blood pressure control alone.

Prevention of Progression in Diabetic Nephropathy

Several studies have clearly shown that in both type 1 and type 2 diabetic
patients who already have microalbuminuria, ACE inhibition is effective in
reducing renal progression. It has been proposed that the benefit is
independent of blood pressure. Nonetheless, in most studies of type 1
diabetes, the treatment has been compared to placebo, and there have been
slight but significant differences in blood
pressure.57 In the
MICRO-HOPE study56
of type 2 diabetic patients, microalbuminuric patients who received ramipril
had reduced progression rate to proteinuria. However, significant differences
existed in blood pressure between groups. In the ABCD
trial,58 aggressive
blood pressure control slowed progression to proteinuria in normotensive but
not hypertensive patients with type 2 diabetes.

In the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria
Study,59 patients
with microalbuminuria were protected from renal progression. Patients who
received 300 mg of irbesartan daily for 24 months had a 70% risk reduction
versus placebo, whereas the blood pressure achieved was basically identical.
In addition, the patients who received high-dose irbesartan had a greater
regression to normoalbuminuria (34%) than did the ones receiving 150 mg of
irbesartan (24%) or placebo (21%). The Microalbuminuria Reduction With
Valsartan (MARVAL)
trial60 compared
the effects of valsartan and amlodipine in 322 patients who had type 2
diabetes and microalbuminuria. After 24 weeks, patients treated with an ARB
had a greater reduction in microalbuminuria and in regression to
normoalbuminuria.

It is in patients with overt diabetic nephropathy (macroalbuminuria and
abnormal GFR) that blood pressure reduction, usually with an ARB or ACE
inhibitor, has dramatically improved the renal prognosis.

In patients with type 1 diabetes, ACE inhibition has been shown to reduce
doubling of serum creatinine (DSC) reaching ESRD, and death: 409 patients with
overt nephropathy were randomized to receive either captopril or placebo for 4
years. Captopril was associated with a 48% risk of DSC, which was thought to
be independent of a small but significant difference in blood pressure between
the groups.61

In type 2 diabetes, two large randomized long-term trials have shown that
ARBs are effective in slowing progression of diabetic nephropathy. In the
Reduction of Endpoints in NIDDM With the Angiotensin Antagonist Losartan
(RENAAL) study,62
1,513 patients were randomized to either losartan or placebo (in addition to
conventional therapy, excluding ACE inhibitors and ARBs) and followed for 3.4
years. Compared to the placebo group, patients who received losartan had a
risk reduction of 25% for DSC and 28% for reaching ESRD. In the Irbesartan
Diabetic Nephropathy Trial
(IDNT),63 1,715
patients were randomized to receive irbesartan, amlodipine, or placebo (in
addition to conventional therapy excluding ACE inhibitors, ARBs, and calcium
channel blockers) and followed for 2.6 years. Irbesartantreated patients had a
risk reduction for DSC of 33% compared to the placebo group and of 37%
compared to the amlodipine group. Furthermore, both irbesartan and losartan
were associated with greater reductions in albumin excretion rates than seen
in other treatment groups. Overall, these studies have shown that
nephroprotection with ACE inhibitors and ARBs occurs over and above what might
be expected with reduction of blood pressure.

These studies have led the ADA to recommend the use of ARBs for the
treatment of patients with type 2 diabetes, proteinuria, and microalbuminuria,
whereas ACE inhibitors are indicated for patients with type 1
diabetes.43 We are
still lacking large trials of ACE inhibition in type 2 diabetic patients with
proteinuria and of ARBs in type 1 diabetes. Despite this lack of trial data,
the National Kidney Foundation has recommended that either ARBs or ACE
inhibitors be used for patients with diabetes regardless of the presence of
hypertension.64
This recommendation is made because both classes of drugs interrupt the RAS,
which is known to be an important mechanism in diabetic nephropathy.
Furthermore, patient intolerance to one class of these drugs may be avoided by
substituting the other class without losing the potential benefit of the RAS
inhibition. Several small studies have suggested that combining ACE inhibitors
and ARBs may afford even more protection or regression of diabetic
nephropathy, but further large trials are needed.

SUMMARY

Following are the key therapeutic strategies for diabetic nephropathy.

Glycemic control to A1C < 7% reduces the appearance of diabetic kidney
disease.

Blood pressure reduction to < 130/80 mmHg with ACE inhibitors or ARBs
reduces the appearance of diabetic nephropathy in type 2 diabetes but is not
proven to do so in type 1 diabetes.

Slowing the progression of diabetic nephropathy has been demonstrated with
blood pressure lowering (to < 130/80mmHg) with ACE inhibition in type 1 and
type 2 diabetes and by ARB treatment in type 2 diabetes.

The protective effect of ACE inhibition or ARB therapy has been shown to be
the result of both blood pressure reduction and direct drug effect.

In patients with diabetic nephropathy and mild to moderate azotemia,
therapy with ACE inhibitors or ARBs may cause up to a 25%increase in serum
creatinine within 4 weeks of initiation of therapy. Increases in serum
potassium may also be seen. The rise in serum creatinine does not nullify the
protective effects of ACE inhibitor or ARB therapy. Serum potassium elevations
may be modified by a low-potassium diet and inclusion of diuretics in the
antihypertensive regimen.

Footnotes

Phillip M. Hall, MD, is a consultant in the Department of Nephrology
and Hypertension at the Cleveland Clinic Foundation in Cleveland,
Ohio.

The DCCT Research Group: The effect of
intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N
Engl J Med329:977
–986, 1993